Pain is a critical problem in health care: it affects millions of individuals, costs billions of dollars, and is a major cause of morbidity, suffering, drug abuse and suicide. The aversive nature of pain is presumably a major cause of suffering and of maladaptive pain-associated behaviors. In addition, it has been suggested that chronic pain has a rewarding component, which may reinforce these behaviors. The CNS circuitry underlying the motivational and aversive aspects of pain has not been identified. However, recent animal research suggests that the CNS circuitry mediating reward is also involved in processing aversive experiences such as pain. The long-term objectives are: I) to identify in humans the regions of CNS reward circuitry involved in the response to acute pain and 2) to assess the effect of exogenous and endogenous opioids on activity in these regions. Functional magnetic resonance imaging (fMRI) experiments will examine activation of reward circuitry (nucleus accumbens, amygdala, sublenticular extended amygdala, ventral tegmentum/periaqueductal gray) by noxious thermal stimuli, morphine and the opioid antagonist naloxone alone and in combination. In addition fMRI will be used to evaluate reward circuitry function during acute oploid withdrawal, and to evaluate how opioid withdrawal alters activity in reward circuitry during painful stimulation. The results of these studies should provide a framework for future experiments to address whether activation of reward circuitry in fact mediates the aversive and rewarding aspects of pain and to investigate how this circuitry is activated in chronic pain patients and opioid addicts.